Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_FGF2)

ABSTRACT: The molecular basis for heterogeneity of cancer-associated fibroblast (CAF) populations remains to be established. We report that fibroblast growth factor (FGF) and transforming growth factor-beta (TGFB) signaling are strong opposite modulators of key CAF effector genes. While FGF activation in normal human dermal fibroblasts (HDFs) induces a number of mitogenic growth factors and metalloproteases, it suppresses expression of pro-fibrotic and cancer-associated extracellular matrix proteins, with TGFB exerting reverse effects. Genetic abrogation or pharmacological inhibition of either pathway results in induction of CAF effector genes responsive to the other, with the ETV1 transcription factor mediating FGF effects and suppressing those of TGFB. This duality of FGF- and TGFB- signaling is reflected in the distinct gene expression profiles of HDFs derived from a large cohort of individuals, multiple Squamous Cell Carcinoma (SCC)-derived CAF strains and stromal fibroblasts underlying premalignant (Actinic Keratoses) and desmoplastic versus non-desmoplastic skin SCC lesions. Functionally, an altered balance between FGF or TGFB signaling, by genetic suppression of either, is sufficient to confer upon HDFs growth enhancing properties on neighboring SCC cells, in vitro and in vivo, in an orthotopic skin cancer model. Thus, activation of heterogeneous CAF populations by deregulation of distinct signaling pathways converges on cancer development with implications of translational significance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122368 | GEO | 2019/07/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (DNFGFR1_affy)

Project description:The molecular basis for heterogeneity of cancer-associated fibroblast (CAF) populations remains to be established. We report that fibroblast growth factor (FGF) and transforming growth factor-beta (TGFB) signaling are strong opposite modulators of key CAF effector genes. While FGF activation in normal human dermal fibroblasts (HDFs) induces a number of mitogenic growth factors and metalloproteases, it suppresses expression of pro-fibrotic and cancer-associated extracellular matrix proteins, with TGFB exerting reverse effects. Genetic abrogation or pharmacological inhibition of either pathway results in induction of CAF effector genes responsive to the other, with the ETV1 transcription factor mediating FGF effects and suppressing those of TGFB. This duality of FGF- and TGFB- signaling is reflected in the distinct gene expression profiles of HDFs derived from a large cohort of individuals, multiple Squamous Cell Carcinoma (SCC)-derived CAF strains and stromal fibroblasts underlying premalignant (Actinic Keratoses) and desmoplastic versus non-desmoplastic skin SCC lesions. Functionally, an altered balance between FGF or TGFB signaling, by genetic suppression of either, is sufficient to confer upon HDFs growth enhancing properties on neighboring SCC cells, in vitro and in vivo, in an orthotopic skin cancer model. Thus, activation of heterogeneous CAF populations by deregulation of distinct signaling pathways converges on cancer development with implications of translational significance.

2019-07-31 | GSE122371 | GEO

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (CAF_vs_Norm_affy)

2019-07-31 | GSE122370 | GEO

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_65_HDF)

2019-07-31 | GSE122369 | GEO

Dual role of CSL (RBP-Jk) and NOTCH1 in cancer-associated fibroblast genome stability and expansion [RNA-seq]

Project description:Genomic instability is a hallmark of cancer. Whether or not it also occurs in cancer-associated fibroblasts (CAFs) is a question of importance for the cancer/stromal cell co-evolution process. We find that DNA damage, telomere shortening and chromosome fusions occur at early times of CAF activation, as triggered by silencing of the CSL/RBP-J-κ gene in primary human dermal fibroblasts (HDFs) from multiple individuals. Similar alterations occur in skin Squamous Cell Carcinoma (SCC) - derived CAFs, in which CSL is down-modulated, versus HDFs from unaffected skin of the same patients. Mechanistically, CSL is part of a telomere protective complex with UPF1, KU70, and KU80 proteins, which fail to bind to telomeres in the absence of CSL. In CAFs, persistent genomic instability is associated with frequent amplification and overexpression of NOTCH1 gene, which is required to suppress DNA damage-induced ATM/P53 activation and growth arrest. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological suppression of NOTCH1 activity suppresses cancer/stromal cell proliferation and expansion.

2019-09-11 | GSE113542 | GEO

Cancer-associated fibroblasts recapitulate phenotypes and functions across tumor types and species

Project description:Cancer-associated fibroblasts (CAFs) are among the most abundant cell types in desmoplastic tumors. However, CAFs are not yet a treatment target in mainstream cancer therapy likely because CAF heterogeneity and their roles in solid tumors remain incompletely understood. Here, we explored CAF heterogeneity via single-cell gene expression and chromatin accessibility in conjunction with spatial transcriptomics. We found that CAF heterogeneity is recapitulated across solid tumor types and species, and CAF subpopulations fall into two functional categories: mechano-responsive and immuno-modulatory. These categories are spatially-distinct and governed by specific changes in chromatin accessibility. Selective disruption of underlying mechanical force or immune signaling results in predictable shifts in subpopulation distributions and impacts tumor growth. Collectively, this research elucidates the spatial dynamics of CAF biology, delineates CAF subpopulation functions, identifies CAF-specific treatment factors, and provides a multimodal -omics framework for understanding the tumor stromal niche.

2023-02-01 | GSE179705 | GEO

Transcriptomic analysis of CAFs with silencing of ANKRD1.

Project description:Stromal cell senescence plays a crucial role in activating cancer-associated fibroblasts (CAFs). The Androgen receptor (AR) function oversees cellular senescence and CAF activation. Here, we identify the mesenchymal-specific transcriptional coregulator ANKRD1 as a key driver of CAF conversion. ANKRD1 is strongly upregulated in CAFs and under direct negative control of AR, and its loss impairs the pro-tumorigenic potential of CAFs. ANKRD1 controls a CAF-specific gene expression program and is associated with poorer survival of HNSCC, lung, and cervical SCC patients. Mechanistically, ANKRD1 binds to the chromatin on CAF gene regulatory regions in a complex with the AP1 transcription factor family. We show that ANKRD1 enhances the AP1 DNA binding activity to CAF gene promoters. Targeting ANKRD1 with the FANA antisense oligonucleotides reverts CAFs into a normal fibroblast, disrupts AP1 complex formation, and blocks CAF’s pro-tumorigenic potential in an orthotopic model of SCC, thus representing an exciting target for stroma-oriented cancer therapy.

2023-11-10 | GSE218214 | GEO

ChIP-seq analysis of primary human dermal fibroblasts overexpressing ANKRD1 in human dermal fibroblasts (HDFs)

2023-11-10 | GSE218204 | GEO

Transcriptomic analysis of human dermal fibroblasts overexpressing ANKRD1.

2023-11-10 | GSE218198 | GEO

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development

Project description:Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development

| PRJNA504805 | ENA

Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [ChIP-seq]

Project description:The age-associated increase of cancer risk has been linked with stromal fibroblast senescence and early steps of Cancer Associated Fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signalling in this context. We show that AR expression is down-modulated in stromal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses, AK) as well as in CAFs from the three major skin cancer types, squamous (SCC) and basal cell (BCC) carcinomas and melanomas. Decreased AR expression is linked to the concomitant down-modulation of CSL, key effector of canonical Notch signalling and global modulator of chromatin configuration, and it can be counteracted by treatment with BET inhibitors, which reverse CAF activation. Functionally, AR gene silencing in dermal fibroblasts results in p53-dependent senescence and induction of key CAF-effector genes, with AR physically converging with CSL in negative control of these genes. The findings are of functional significance as, in an orthotopic model of skin cancer, dermal fibroblasts with AR loss enhance significantly tumorigenicity of SCC and melanoma cells. As such, the findings establish AR as a novel potential target for stroma-focused cancer prevention and treatment.

2018-08-28 | GSE107320 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data